Beta-Amyloid (Abeta) is associated with age-related cognitive decline, neurotoxicity and synaptic failure in Alzheimer's disease (AD). Significant progress has been made in understanding the genetic factors and cellular mechanisms contributing to Abeta-induced neurotoxicity. However, the mechanisms responsible for Abeta-induced synaptic dysfunction prior to cell death are largely unknown, and finding safe and effective therapeutic interventions to reverse Abeta-related early AD pathology remains a great challenge. We previously showed that acute application of Abeta inhibited hippocampal long-term potentiation (LTP), a synaptic model of learning and memory, and that this effect was associated with altered intracellular Ca2+ signaling leading to activation of a Ca2+-dependent protein phosphatase calcineurin. Interestingly, we observed in several model systems that neurotrophin 4 and brain-derived neurotrophic factor rescued Abeta- induced deficits in LTP and synaptic transmission. Based on the preliminary data, we hypothesize that a focal point for the neurotrophin (NT)- Abeta interaction is Ca2+ and calmodulin-dependent protein kinase II (CaMKII). Abeta inhibits CaMKII activation via enhanced calcineurin activity, whereas NT counteracts Abeta action by stimulating CaMKII and enhancing the function and synaptic targeting of the AMPA type of glutamate receptors. In addition, NT is known to promote neuronal differentiation, survival and plasticity through two major kinase pathways, mitogen-activated protein kinase (MAPK) and phosphoinositide kinase 3 (PI3K). These two kinase pathways may contribute to the NT rescue by enhancing AMPA receptor function or promoting gene transcription required for both synaptic plasticity and neuronal survival. These hypotheses will be tested using a combination of electrophysiological, biochemical, immunocytochemical and molecular genetic approaches. We will further examine NT- Abeta interactions in regulating multiple forms of hippocampal synaptic plasticity;determine the synaptic locus and mechanisms underlying their opposing effects;and analyze the role of CaMKII, MAPK and PI3K in the NT rescue using various pharmacological, molecular and genetic manipulations. The results may provide new insights into synaptic mechanisms for Abeta action and the therapeutic potentials of trkB-acting NT for early AD.